The present invention is directed to compounds that are alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones. In particular, this invention is directed to phenyl substituted 1,8-naphthyridin-4(1H)-ones which are phosphodiesterase-4 inhibitors wherein the phenyl group is at the 1-position and contains a 2-alkyne substituent group further optionally substituted.
Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 3xe2x80x2,5xe2x80x2-cyclic monophosphate, xe2x80x9ccAMPxe2x80x9d or xe2x80x9ccyclic AMPxe2x80x9d) is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.
Phosphodiesterases (xe2x80x9cPDExe2x80x9d) are a family of enzymes that metabolize 3xe2x80x2,5xe2x80x2 cyclic nucleotides to 5xe2x80x2 nucleoside monophosphates, thereby terminating cAMP second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 (xe2x80x9cPDE4xe2x80x9d, also known as xe2x80x9cPDE-IVxe2x80x9d), which is a high affinity, cAMP specific, type IV PDE, has generated interest as potential targets for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist as at lease four isoenzymes, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in allergic and/or inflammatory responses. Thus, it is believed that inhibition of PDE4, particularly the specific PDE4 isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms. It would be desirable to provide novel compounds and compositions that inhibit PDE4 activity.
A major concern with the use of PDE4 inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C. Burnouf et al., (xe2x80x9cBurnoufxe2x80x9d), Ann. Rep. In Med. Chem., 33:91-109(1998). B. Hughes et al., Br. J.Pharmacol., 118:1183-1191(1996); M. J. Perry et al., Cell Biochem. Biophys., 29:113-132(1998); S. B. Christensen et al., J.Med. Chem., 41:821-835(1998); and Burnouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds. As described in M. D. Houslay et al., Adv. In Pharmacol., 44:225-342(1998) and D. Spina et al., Adv. In Pharmacol., 44:33-89(1998), there is great interest and research of therapeutic PDE4 inhibitors.
International Patent Publication WO9422852 describes quinolines as PDE4 inhibitors. International Patent Publication WO9907704 describes 1-aryl-1,8-naphthylidin-4-one derivatives as PDE4 inhibitors.
A.H. Cook, et al., J.Chem. Soc., 413-417(1943) describes gamma-pyridylquinolines. Other quinoline compounds are described in Kei Manabe et al., J.Org. Chem., 58(24):6692-6700(1993); Kei Manabe et al., J.Am. Chem. Soc., 115(12):5324-5325(1993); and Kei Manabe et al., J.Am. Chem. Soc., 114(17):6940-6941(1992).
Compounds that include ringed systems are described by various investigators as effective for a variety of therapies and utilities. For example, International Patent Publication No. WO 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, U.S. Pat. No. 5,736,297 describes ring systems useful as a photosensitive composition.
U.S. Pat. Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, and International Patent Publication WO 95/35283 describe PDE4 inhibitors that are tri-substituted aryl or heteroaryl phenyl derivatives. U.S. Pat. No. 5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S. Pat. No. 5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827 describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S. Pat. No. 5,780,478 describes PDE4 inhibitors that are tetra-substituted phenyl derivatives. International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. U.S. Pat. No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
However, there remains a need for novel compounds and compositions that therapeutically inhibit PDE4 with minimal side effects.
The present invention is directed to alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones represented by Formula (I): 
or pharmaceutically acceptable salts thereof, which are phosphodiesterase-4 inhibitors.
This invention also provides a pharmaceutical composition which includes an effective amount of the novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones and a pharmaceutically acceptable carrier. This invention further provides a method of treatment in mammals of, for example, i) Pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, adult respiratory distress syndrome, and infant respiratory distress syndrome, ii) Gastrointestinal disorders such as ulcerative colitis, Crohn""s disease, and hypersecretion of gastric acid, iii) Infectious diseases such as bacterial, fungal or viral induced sepsis or septic shock, endotoxic shock (and associated conditions such as laminitis and colic in horses), and septic shock, iv) Neurological disorders such as spinal cord trauma, head injury, neurogenic inflammation, pain, and reperfusion injury of the brain, v) Inflammatory disorders such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, vi) Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) Psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) Neurodegenerative disorders such as Parkinson disease, Alzheimer""s disease, acute and chronic multiple sclerosis, ix) Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissues, xi) Metabolic disorders such as diabetes insipidus, xii) Bone disorders such as osteoporosis, xiii) Cardiovascular disorders such as arterial restenosis, atherosclerosis, reperfusion injury of the myocardium, and xiv) Other disorders such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, and cachexiaxe2x80x94maladies that are amenable to amelioration through inhibition of the PDE4 isoenzyme and the resulting elevated cAMP levelsxe2x80x94by the administration of an effective amount of the novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones or a precursor compound which forms in vivo the novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones which are phosphodiesterase-4 inhibitors.
A compound of this invention is represented by Formula (I): 
or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C1-6alkyl or xe2x80x94C3-6cycloalkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), xe2x80x94(C0-6alkyl)SOnxe2x80x94(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(CO6alkyl)(CO6alkyl), xe2x80x94(C0-6alkyl)SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90NOxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent, H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94NHSOnxe2x80x94(C1-6alkyl), xe2x80x94NHC(O)C1-6alkyl, xe2x80x94NHC(O)-aryl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, xe2x80x94N(C0-6alkyl)(C0-6alkyl), or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is absent, H, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or xe2x80x94N(C0-6alkyl)(C0-6alkyl) substituents;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents; and
R8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or oxides thereof when R8 is a heteroaryl; or H, xe2x80x94C1-6alkyl, or xe2x80x94C3-6cycloalkyl, and any alkyl is optionally substituted with 1-6 independent halogen, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94N(C3-7cycloalkyl)(C0-6alkyl), xe2x80x94N(C3-7cycloalkyl)(C3-7cycloalkyl), N-heterocycloC4-7alkyl, xe2x80x94SOnxe2x80x94(C1-6alkyl), xe2x80x94SOnxe2x80x94(aryl), or xe2x80x94OH substituents.
In one aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C1-6alkyl or xe2x80x94C3-6cycloalkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent;
n is 0, 1, or 2;
R3 is absent;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents; and
R8 is H.
In a second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C1-6alkyl or xe2x80x94C3-6cycloalkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)-SOnxe2x80x94(C1-6alkyl), xe2x80x94(C0-6alkylxe2x80x94SOnxe2x80x94(aryl), phenyl, heteroaryl, or heterocycloC37alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent, H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94NHSOnxe2x80x94(C1-6alkyl), xe2x80x94NHC(O)xe2x80x94C1-6alkyl, xe2x80x94NHC(O)-aryl, xe2x80x94C(O)C0-6alkyl, xe2x80x94C(O)Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, xe2x80x94N(C0-6alkyl)(C0-6alkyl), or xe2x80x94C(O)xe2x80x94Oxe2x80x94C0-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is absent, H, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or xe2x80x94N(C0-6alkyl)(C0-6alkyl) substituents;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents; and
R8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or oxides thereof when R8 is a heteroaryl.
In an embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C 16alkyl or xe2x80x94C3-6cycloalkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94(C0-6alkyl)SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent, H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94NHSOnxe2x80x94(C1-6alkyl), xe2x80x94NHC(O)xe2x80x94C1-6alkyl, xe2x80x94NHC(O)-aryl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnC1-6alkyl), wherein the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, xe2x80x94N(C0-6alkyl)(C0-6alkyl), or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is absent, H, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or xe2x80x94N(C0-6alkyl)(C0-6alkyl) substituents;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents; and
R8 is phenyl.
In another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C1-6alkyl or xe2x80x94C3-6cycloalkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnC1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent, H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94NHSOnC1-6alkyl), xe2x80x94NHC(O)C1-6alkyl, xe2x80x94NHC(O)-aryl, xe2x80x94C(O)C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)SOnC1-6alkyl), wherein the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, xe2x80x94N(C0-6alkyl)(C0-6alkyl), or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is absent, H, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or xe2x80x94N(C0-6alkyl)(C0-6alkyl) substituents;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents; and
R8 is pyridyl, or oxides thereof.
In yet another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C1-6alkyl or xe2x80x94C3-6cycloalkyl;
R 1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnC1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent, H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94NHSOnxe2x80x94(C1-6alkyl), xe2x80x94NHC(O)C1-6alkyl, xe2x80x94NHC(O)-aryl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, xe2x80x94N(C0-6alkyl)(C0-6alkyl), or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is absent, H, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or xe2x80x94N(C0-6alkyl)(C0-6alkyl) substituents;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents; and
R8 is quinolinyl, or oxides thereof.
In still another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C1-6alkyl or xe2x80x94C3-6cycloalkyl;
R1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)SOnxe2x80x94(C1-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent, H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94NHSOnC1-6alkyl), xe2x80x94NHC(O)xe2x80x94C1-6alkyl, xe2x80x94NHC(O)-aryl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)SOnC1-6alkyl), wherein the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, xe2x80x94N(C0-6alkyl)(C0-6alkyl), or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or H substituents;
n is 0, 1, or 2;
R3 is absent, H, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or xe2x80x94N(C0-6alkyl)(C0-6alkyl) substituents;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents; and
R8 is thienyl, or oxides thereof.
In another embodiment of the second aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C1-6alkyl or xe2x80x94C3-6cycloalkyl;
R 1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)xe2x80x94SOnC1-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnaryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent, H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94NHSOnxe2x80x94(C1-6alkyl), xe2x80x94NHC(O)C1-6alkyl, xe2x80x94NHC(O)-aryl, xe2x80x94C(O)C1-6alkyl, xe2x80x94C(O)Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, xe2x80x94N(C0-6alkyl)(C0-6alkyl), or xe2x80x94C(O)-Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is absent, H, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or xe2x80x94N(C0-6alkyl)(C0-6alkyl) substituents;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or H substituents; and
R8 is thiazolyl, or oxides thereof.
In a third aspect, a compound of this invention is represented by Formula (1) or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C1-6alkyl or xe2x80x94C3-6cycloalkyl;
R 1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)SOnxe2x80x94(C1-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent, H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94NHSOnxe2x80x94(C1-6alkyl), xe2x80x94NHC(O)xe2x80x94C1-6alkyl, xe2x80x94NHC(O)-aryl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)SOnxe2x80x94(C1-6alkyl), wherein the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, xe2x80x94N(C0-6alkyl)(C0-6alkyl), or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is absent, H, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or xe2x80x94N(C0-6alkyl)(C0-6alkyl) substituents;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or H substituents; and
R8 is xe2x80x94C3-6cycloalkyl, optionally substituted with 1-6 independent halogen, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94N(C3-7cycloalkyl)(C0-6alkyl), xe2x80x94N(C3-7cycloalkyl)(C3-7cycloalkyl), N-heterocycloC4-7alkyl, xe2x80x94SOnxe2x80x94(C1-6alkyl), xe2x80x94SOnxe2x80x94(aryl), or H substituents.
In a fourth aspect, a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
R is H, xe2x80x94C1-6alkyl or xe2x80x94C3-6cycloalkyl;
R 1 is H, or a xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkoxy, xe2x80x94C2-6alkenyl, xe2x80x94C3-6alkynyl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)-aryl, xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), xe2x80x94(C0-6alkyl)SOnxe2x80x94(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94(C0-6alkyl)xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, or halogen substituents;
R2 is absent, H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C3-6cycloalkyl, xe2x80x94C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), xe2x80x94C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, xe2x95x90Nxe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94Oxe2x80x94Nxe2x95x90C1-6alkyl, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94NHSOnxe2x80x94(C1-6alkyl), xe2x80x94NHC(O)xe2x80x94C1-6alkyl, xe2x80x94NHC(O)-aryl, xe2x80x94C(O)xe2x80x94C1-6alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, xe2x80x94C1-6alkyl(xe2x95x90Nxe2x80x94OH), xe2x80x94C(Nxe2x95x90NOH)C1-6alkyl, xe2x80x94C0-6alkyl(oxy)C1-6alkyl-phenyl, xe2x80x94SOnNH(C0-6alkyl), or xe2x80x94(C0-6alkyl)SOnC1-6alkyl), wherein the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, hydroxy, xe2x80x94N(C0-6alkyl)(C0-6alkyl), or xe2x80x94C(O)xe2x80x94Oxe2x80x94C1-6alkyl, and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents;
n is 0, 1, or 2;
R3 is absent, H, OH, xe2x80x94N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, wherein any alkyl is optionally substituted with 1-6 independent halogen, OH, or xe2x80x94N(C0-6alkyl)(C0-6alkyl) substituents;
R4, R5, R6, and R7 each independently is H, halogen, xe2x80x94C1-6alkyl, xe2x80x94C1-6alkoxy, xe2x80x94SOnxe2x80x94(C1-6alkyl), nitro, CN, or xe2x80x94N(C0-6alkyl)(C0-6alkyl), and any alkyl is optionally substituted with 1-6 independent halogen or xe2x80x94OH substituents; and
R8 is xe2x80x94C1-6alkyl, optionally substituted with 1-6 independent halogen, xe2x80x94N(C0-6alkyl)(C0-6alkyl), xe2x80x94N(C3-7cycloalkyl)(C0-6alkyl), xe2x80x94N(C3-7cycloalkyl)(C3-7cycloalkyl), N-heterocycloC4-7alkyl, xe2x80x94SOnxe2x80x94(C1-6alkyl), xe2x80x94SOnxe2x80x94(aryl), or xe2x80x94OH substituents.
As used herein, xe2x80x9calkylxe2x80x9d as well as other groups having the prefix xe2x80x9calkxe2x80x9d such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. xe2x80x9cAlkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d and other like terms include carbon chains containing at least one unsaturated C-C bond.
The term xe2x80x9ccycloalkylxe2x80x9d means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl, adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyl and the like. Similarly, xe2x80x9ccycloalkenylxe2x80x9d means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.
The term xe2x80x9ccycloalkyloxyxe2x80x9d unless specifically stated otherwise includes a cycloalkyl group connected to the oxy connecting atom.
The term xe2x80x9calkoxyxe2x80x9d unless specifically stated otherwise includes an alkyl group connected to the oxy connecting atom.
The term xe2x80x9carylxe2x80x9d unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl.
The term xe2x80x9caryloxyxe2x80x9d unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl, connected through the oxy connecting atom to the connecting site.
The term xe2x80x9cC0-6alkylxe2x80x9d includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent when the alkyl is a terminus moiety. An alkyl with no carbon atoms is a direct bond when the alkyl is a bridging moiety.
The term xe2x80x9cheteroxe2x80x9d unless specifically stated otherwise includes one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The heteroatoms replace ring carbon atoms. Thus, for example, a heterocycloC5alkyl is a five membered ring containing from 5 to no carbon atoms.
Examples of heteroaryl include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.
The term xe2x80x9cheteroaryloxyxe2x80x9d unless specifically stated otherwise describes a heteroaryl group connected through an oxy connecting atom to the connecting site.
Examples of heteroaryl(C1-6)alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.
Examples of heterocycloC3-7alkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
The term xe2x80x9cN-heterocycloC4-7alkylxe2x80x9d describes nonaryl heterocyclic compounds having 3-6 carbon atoms and one nitrogen atom forming the ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, and perhydroazepinyl.
Examples of aryl(C1-6)alkyl include, for example, phenyl(C1-6)alkyl, and naphthyl(C1-6)alkyl.
Examples of heterocycloC3-7alkylcarbonyl(C1-6)alkyl include, for example, azetidinyl carbonyl(C1-6)alkyl, pyrrolidinyl carbonyl(C1-6)alkyl, piperidinyl carbonyl(C1-6)alkyl, piperazinyl carbonyl(C1-6)alkyl, morpholinyl carbonyl(C1-6)alkyl, and thiomorpholinyl carbonyl(C1-6)alkyl.
The term xe2x80x9caminexe2x80x9d unless specifically stated otherwise includes primary, secondary and tertiary amines.
Unless otherwise stated, the term xe2x80x9ccarbamoylxe2x80x9d is used to include xe2x80x94NHC(O)OC1-4alkyl, and xe2x80x94OC(O)NHC1-4alkyl.
The term xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine and iodine atoms.
The term xe2x80x9coptionally substitutedxe2x80x9d is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring. Further, the substitution can be made at any of the groups. For example, substituted aryl(C1-6)alkyl includes substitution on the aryl group as well as substitution on the alkyl group.
The term xe2x80x9coxidexe2x80x9d of heteroaryl groups is used in the ordinary well-known chemical sense and include, for example, N-oxides of nitrogen heteroatoms.
Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers.
Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included.
During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be mixtures of stereoisomers.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
The pharmaceutical compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal anti-inflammatory drugs (xe2x80x9cNSAIDxe2x80x9d), and ix) M2/M3 antagonists. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
Dosage levels from about 0.001mg/kg to about 140mg/kg of body weight per day are useful in the treatment of conditions such as i) Pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, adult respiratory distress syndrome, and infant respiratory distress syndrome, ii) Gastrointestinal disorders such as ulcerative colitis, Crohn""s disease, and hypersecretion of gastric acid, iii) Infectious diseases such as bacterial, fungal or viral induced sepsis or septic shock, endotoxic shock (and associated conditions such as laminitis and colic in horses), and septic shock, iv) Neurological disorders such as spinal cord trauma, head injury, neurogenic inflammation, pain, and reperfusion injury of the brain, v) Inflammatory disorders such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, vi) Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) Psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) Neurodegenerative disorders such as Parkinson disease, Alzheimer""s disease, acute and chronic multiple sclerosis, ix) Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissues, xi) Metabolic disorders such as diabetes insipidus, xii) Bone disorders such as osteoporosis, xiii) Cardiovascular disorders such as arterial restenosis, atherosclerosis, reperfusion injury of the myocardium, and xiv) Other disorders such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, and cachexiaxe2x80x94which are responsive to PDE4 inhibition, or alternatively about 0.05 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 mg to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 2.5 g per patient per day. Further, it is understood that the PDE4 inhibiting compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.01 mg to about 1000 mg of the active ingredient, typically 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
In practice, the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
The compounds and pharmaceutical compositions of this invention have been found to exhibit biological activity as PDE4 inhibitors. Accordingly, another aspect of the invention is the treatment in mammals of, for example, i) Pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, adult respiratory distress syndrome, and infant respiratory distress syndrome, ii) Gastrointestinal disorders such as ulcerative colitis, Crohn""s disease, and hypersecretion of gastric acid, iii) Infectious diseases such as bacterial, fungal or viral induced sepsis or septic shock, endotoxic shock (and associated conditions such as laminitis and colic in horses), and septic shock, iv) Neurological disorders such as spinal cord trauma, head injury, neurogenic inflammation, pain, and reperfusion injury of the brain, v) Inflammatory disorders such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, vi) Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) Psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) Neurodegenerative disorders such as Parkinson disease, Alzheimer""s disease, acute and chronic multiple sclerosis, ix) Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissues, xi) Metabolic disorders such as diabetes insipidus, xii) Bone disorders such as osteoporosis, xiii) Cardiovascular disorders such as arterial restenosis, atherosclerosis, reperfusion injury of the myocardium, and xiv) Other disorders such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, and cachexiaxe2x80x94maladies that are amenable to amelioration through inhibition of the PDE4 isoenzyme and the resulting elevated cAMP levelsxe2x80x94by the administration of an effective amount of the compounds of this invention. The term xe2x80x9cmammalsxe2x80x9d includes humans, as well as other animals such as, for example, dogs, cats, horses, pigs, and cattle. Accordingly, it is understood that the treatment of mammals other than humans is the treatment of clinical correlating afflictions to those above recited examples that are human afflictions.
Further, as described above, the compound of this invention can be utilized in combination with other therapeutic compounds. In particular, the combinations of the PDE4 inhibiting compound of this invention can be advantageously used in combination with i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) H1 (histamine) receptor antagonists and ix) beta 2 adrenoceptor agonist.
Thus, for example, pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, infant respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, adult respiratory distress syndrome, and infant respiratory distress syndrome can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Gastrointestinal disorders such as ulcerative colitis, Crohn""s disease, and hypersecretion of gastric acid can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Infectious diseases such as bacterial, fungal or viral induced sepsis or septic shock, endotoxic shock (and associated conditions such as laminitis and colic in horses), and septic shock can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Neurological disorders such as spinal cord trauma, head injury, neurogenic inflammation, pain, and reperfusion injury of the brain can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Inflammatory disorders such as psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Psychiatric disorders such as depression, memory impairment, and monopolar depression can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Neurodegenerative disorders such as Parkinson disease, Alzheimer""s disease, acute and chronic multiple sclerosis can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissues can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Metabolic disorders such as diabetes insipidus can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
Bone disorders such as osteoporosis, cardiovascular disorders such as arterial restenosis, atherosclerosis, reperfusion injury of the myocardium, and other disorders such as chronic glomerulonephritis, vernal conjunctivitis, transplant rejection and graft versus host disease, and cachexia can be conveniently treated with capsules, cachets or tablets each containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.
Whole blood provides a protein and cell-rich milieu appropriate for the study of biochemical efficacy of anti-inflammatory compounds such as PDE4-selective inhibitors. Normal non-stimulated human blood does not contain detectable levels of TNF-xcex1 and LTB4. Upon stimulation with LPS, activated monocytes express and secrete TNF-xcex1 up to 8 hours and plasma levels remain stable for 24 hours. Published studies have shown that inhibition of TNF-xcex1 by increasing intracellular cAMP via PDE4 inhibition and/or enhanced adenylyl cyclase activity occurs at the transcriptional level. LTB4 synthesis is also sensitive to levels of intracellular cAMP and can be completely inhibited by PDE4-selective inhibitors. As there is little LTB4 produced during a 24 hour LPS stimulation of whole blood, an additional LPS stimulation followed by fMLP challenge of human whole blood is necessary for LTB4 synthesis by activated neutrophils. Thus, by using the same blood sample, it is possible to evaluate the potency of a compound on two surrogate markers of PDE4 activity in the whole blood by the following procedure.
Fresh blood was collected in heparinized tubes by venipuncture from healthy human volunteers (male and female). These subjects had no apparent inflammatory conditions and had not taken any NSAIDs for at least 4 days prior to blood collection. 500 xcexcL aliquots of blood were pre-incubated with either 2 xcexcL of vehicle (DMSO) or 2 xcexcL of test compound at varying concentrations for 15 minutes at 37xc2x0 C. This was followed by the addition of either 10 xcexcL vehicle (PBS) as blanks or 10 xcexcL LPS (1 xcexcg/mL final concentration, #L-2630 (Sigma Chemical Co., St. Louis, Mo.) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After 24 hours of incubation at 37xc2x0 C., another 10 xcexcL of PBS (blank) or 10 xcexcL of LPS (1 xcexcg/mL final concentration) was added to blood and incubated for 30 minutes at 37xc2x0 C. The blood was then challenged with either 10 xcexcL of PBS (blank) or 10 xcexcL of fMLP (1 xcexcM final concentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37xc2x0 C. The blood samples were centrifuged at 1500xc3x97g for 10 minutes at 4xc2x0 C. to obtain plasma. A 50 xcexcL aliquot of plasma was mixed with 200 xcexcL methanol for protein precipitation and centrifuged as above. The supernatant was assayed for LTB4 using an enzyme immunoassay kit (#520111 from Cayman Chemical Co., Ann Arbor, Mich.) according to the manufacturer""s procedure. TNF-xcex1 was assayed in diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, N.J.) according to manufacturer""s procedure. IC50 values should be less than about 5 xcexcM, advantageously less than about 2.5 xcexcM. The IC50 values of Examples 1 to 33 ranged from 0.01 xcexcM to 2.4 xcexcM.
Compounds of the invention have been tested for effects on an IgE-mediated allergic pulmonary inflammation induced by inhalation of antigen by sensitized guinea pigs. Guinea pigs were initially sensitized to ovalbumin under mild cyclophosphamide-induced immunosuppression, by intraperitoneal injection of antigen in combinations with aluminum hydroxide and pertussis vaccine. Booster doses of antigen were given two and four weeks later. At six weeks, animals were challenged with aerosolized ovalbumin while under cover of an intraperitoneally administered anti-histamine agent (mepyramine). After a further 48 h, bronchial alveolar lavages (BAL) were performed and the numbers of eosinophils and other leukocytes in the BAL fluids were counted. The lungs were also removed for histological examination for inflammatory damage. Administration of compounds of the Examples (0.001-10 mg/kg i.p. or p.o.), up to three times during the 48 h following antigen challenge, lead to a significant reduction in the eosinophilia and the accumulation of other inflammatory leukocytes.
Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IV cAMP-specific phosphodiesterases were screened in a 96-well plate format as follows:
In a 96 well-plate at 30xc2x0 C. the test compound was added (dissolved in 2 xcexcL DMSO), 188 xcexcL of substrate buffer containing [2,8-3H] adenosine 3xe2x80x2,5xe2x80x2-cyclic phosphate (cAMP, 100 nM to 50 xcexcM), 10 mM MgCl2, 1 mM EDTA, 50 mM Tris, pH 7.5. The reaction was initiated by the addition of human recombinant PDE4 (the amount was controlled so that 10% product was formed in 10 min.). The reaction was stopped after 10 min. by the addition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc., Piscataway, N.J.). The product AMP generated was quantified on a Wallac Microbeta(copyright) 96-well plate counter (EGandG Wallac Co., Gaithersburg, Md.). The signal in the absence of enzyme was defined as the background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with the background subtracted. Percentage of inhibition was calculated accordingly. IC50 value was approximated with a non-linear regression fit using the standard 4-parameter/multiple binding sites equation from a ten point titration.
The IC50 values of Examples 1 to 33 were determined with 100 nM cAMP using the purified GST fusion protein of the human recombinant phosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9 expression system. IC50 values should be less than about 1000 nM, advantageously less than about 250 nM, and even more advantageously less than about 100 nM. The IC50 values of Examples 1 to 33 ranged from 0.1 nM to 90.0 nM.
The Examples that follow are intended as an illustration of certain preferred embodiments of the invention and no limitation of the invention is implied.
Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room or ambient temperaturexe2x80x94that is, at a temperature in the range of 18-25xc2x0 C. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm Hg) with a bath temperature of up to 60xc2x0 C. The course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only. Melting points are uncorrected and xe2x80x9cdxe2x80x9d indicates decomposition. The melting points given are those obtained for the materials prepared as described. Polymorphism may result in isolation of materials with different melting points in some preparations. The structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. When given, yields are for illustration only. When given, NMR data is in the form of delta (xcex4) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc. In addition, xe2x80x9cArxe2x80x9d signifies an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations have also been used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)),mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
Compounds of the present invention can be prepared according to the following methods. The substituents are the same as in Formula I except where defined otherwise.
In a first method outlined below in Scheme 1, an appropriately substituted derivative of ethyl 2-chloronicotinoyl acetate of formula II is reacted with 1.5 equivalents of triethyl orthoformate and 5 equivalents of acetic anhydride at 130xc2x0 C., and after removal of the volatile components the crude 2-chloronicotinoyl acrylate of formula III is immediately reacted with 1.2 equivalents of an appropriately substituted haloaryl amine of formula IV, such as, for example 3-bromoaniline, in a halogenated hydrocarbon solvent such as methylene chloride at a temperature of 0xc2x0 C. to room temperature. After an appropriate reaction time ranging from 2 to 24 hours the resulting 3-arylamino acrylate of formula V is obtained by evaporation of the solvent and may be further purified by chromatography on silica gel or crystallization from an appropriate solvent. The compound of formula V may alternatively be used without further purification in the following step. Cyclization of the compound of formula V to the 1-haloaryl-1,4-dihydro[1,8]naphthyridin-4-one carboxylate of formula VI is effected by treatment with a small excess of a strong base such as an alkali metal hydride, for example sodium hydride, in an appropriate solvent such as tetrahydrofuran at a starting temperature of 0xc2x0 C. with warming to room temperature if required to complete the process. The product of formula VI is isolated in crude form by dilution with a large volume of water followed by filtration or by extraction into an appropriate organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in an appropriate solvent followed by filtration.
The ester product of formula VI thus obtained can be hydrolyzed to the corresponding carboxylic acid derivative under basic conditions, using an aqueous solution of an alkali base such as an alkali carbonate or preferably sodium or potassium hydroxide, with an organic cosolvent such as tetrahydrofuran or a primary, secondary or tertiary alkanol, such as methanol or ethanol, or a combination thereof at temperatures ranging from room temperature to reflux temperature for the appropriate time. The resultant carboxylic acid is isolated in crude form following acidification using an aqueous solution of an inorganic acid such as hydrochloric, sulfuric or a similar acid, and filtration or extraction into an appropriate organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in an appropriate solvent followed by filtration. The carboxylic acid is then transformed into the appropriate primary, secondary or tertiary amide analog of formula VII by any general procedure well known to the organic chemist, preferably via initial transformation into a mixed anhydride by treatment with a small excess, usually 1.25 equivalents, of an appropriate alkyl chloroformate such as ethyl or isobutyl chloroformate, in the presence of a larger excess, usually 2.5 equivalents, of a tertiary organic amine such as triethylamine or N,N-diisopropylethylamine in an organic solvent such as tetrahydrofuran at low temperature, preferably 0xc2x0 C. for a period of 30 minutes to 3 hours. Alternatively, the acid may be transformed into an acid chloride through the action of, for instance, thionyl chloride. An excess, usually 5 or more equivalents, of an appropriate primary or secondary amine or of an aqueous solution of ammonium hydroxide is then added and the reaction is allowed to proceed at a temperature ranging from 0xc2x0 C. to room temperature for an appropriate length of time, usually 1-24 hours. The desired amide of formula VII is then isolated in crude form by precipitation with water and filtration or extraction into an appropriate organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by chromatography on silica gel, crystallization or prolonged stirring in an appropriate solvent followed by filtration. Alternatively, an amide of formula VII can be obtained from an acid and an amine via an appropriate coupling reagent, such as carbonyldiimidazole (CDI). In cases where the amide moiety is 2,6-dichloropyridin-4-yl a different procedure is used in which the anion of 4-amino-3,5-dichloropyridine is generated at low temperature, preferably at 0xc2x0 C. using a strong alkali hydride such as sodium hydride in a solvent such as tetrahydrofuran, and reacted with the acid chloride of a carboxylic acid (from hydrolysis of an ester of formula VI) generated by an appropriate known procedure, usually by the action of oxalyl chloride activated by a catalytic amount of N,N-dimethylformamide in a solvent such as tetrahydrofuran.
For the synthesis of compounds of formula I, an amide compound of formula VII is reacted with an appropriately substituted acetylene of formula VIII under the catalysis of a transition metal species such as bis(triphenylphosphine)palladium (II) chloride or [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in an appropriate solvent such as THF or DMF in the presence of triethylamine and a cuprous salt such as cuprous iodide, at a temperature ranging from room temperature to reflux for an appropriate period of time. Alternatively, an ester compound of formula VI can be reacted in the same manner to afford an ester compound of formula IX, which is submitted to the hydrolysis and amidation processes described above leading to a compound of formula I. 
In a second approach to the synthesis of compounds of formula I, outlined below in Scheme 2, an amide of formula VII is reacted with trimethylsilylacetylene under the catalysis of a transition metal species such as bis(triphenylphosphine)palladium (II) chloride or [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in an appropriate solvent such as THF or DMF in the presence of triethylamine and a cuprous salt such as cuprous iodide, at a temperature ranging from room temperature to reflux for an appropriate period of time. The resulting compound is liberated from the TMS protecting group under the action of an aqueous solution of an alkali hydroxide such as sodium or potassium hydroxide in the presence of an organic cosolvent such as methanol, or alternatively by treatment with a source of fluoride such as tetrabutylammonium fluoride in THF solution to yield an acetylene derivative of formula X.
Such a compound is reacted with an appropriate alkyl or aryl or heteroaryl halide of formula XI under the catalysis of a transition metal species such as bis(triphenylphosphine)palladium (II) chloride or [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in an appropriate solvent such as THF or DMF in the presence of triethylamine and a cuprous salt such as cuprous iodide, at a temperature ranging from room temperature to reflux for an appropriate period of time, to yield a compound of formula I. Alternatively, an ester compound of formula VI can be processed in the same manner to afford an ester compound of formula IX, which is submitted to the hydrolysis and amidation processes described above leading to a compound of formula I. 
In an alternative approach to acetylenic esters of formula IX or XII (where R8=H), outlined in Scheme 3, an appropriately substituted 2-chloronicotinoyl chloride of formula XIII is reacted with a 3-dialkylaminoacrylate, for example ethyl 3-dimethylaminoacrylate, in the presence of a tertiary amine such as triethylamine, in a solvent such as toluene at an appropriate temperature to afford a 3-dialkylamino acrylate of formula XIV. Such a substance is reacted with an appropriately substituted 3-aminophenylacetylene derivative of formula XV in a solvent such as DMF or acetonitrile in the presence of an inorganic base such as potassium carbonate at an appropriate temperature to yield an acetylenic ester of formula IX or XII (where R8=H). 
The majority of the acetylenic reagents of formula VIII used in this invention were of commercial sources. Where required, appropriately substituted acetylenes of formula VIII were synthesized as outlined in Scheme 4, preferentially from corresponding halides (XI) by initial condensation with trimethylsilylacetylene under the catalysis of a transition metal species, followed by removal of the TMS group, as described above in Scheme 2 in the preparation of compounds of type X or XII. Where the substituent R8 on the acetylene is a secondary or tertiary alcohol, the anion of trimethylsilylacetylene is generated at low temperature, using a an alkyllithium base such as n-butyllithium, and it can be reacted with an appropriately substituted aldehyde or ketone to afford the desired reagent of formula VIII. 
The following are examples of syntheses of aryl and heteroaryl halides corresponding to compounds of formula XI bearing a secondary or tertiary alcohol as substituent. For pyridine derivatives (Scheme 5), a halogen-substituted pyridyl carboxylate of formula XVI can be reacted with an organometallic species such as a Grignard reagent to afford a tertiary alcohol of formula XVII. Alternatively, a dibromopyridine substrate of formula XVIII may be monometallated using an alkyllithium species such as n-butyllithium, followed by addition of an aldehyde or ketone to yield a compound of formula XVII. 
A thiophene derivative of formula XX results from the reaction of a halogen substituted thiophene aldehyde or ketone of formula XIX (Scheme 6) with an organometallic species such as a Grignard reagent. 
For the synthesis of the thiazole derivatives of formula XXII, described in Scheme 7, initial metallation of thiazole using an alkyllithium species such as n-butyllithium, followed by addition of an aldehyde or ketone yields a 2-thiazolyl secondary or tertiary alcohol which is suitably protected, for example as a SEM ether of formula XXI. Subsequent bromination leads to introduction of a bromo atom at the 5-position with concomitant removal of the protective group, resulting in a compound of formula XXII. 
Where required, pyridine derivatives can be oxidized to the corresponding N-oxides using well-known reagents such as m-chloroperoxybenzoic acid or magnesium monoperoxyphthalate.